HIV-infected patients demonstrate changes in fat distribution and metabolic abnormalities which increase cardiovascular risk. GH secretion is reduced in inverse association with excess visceral adiposity in HIV- infected patients. Physiological studies have shown reduced GHRH as one mechanism in this regard. We have now shown significant effects of exogenous GHRH, to result in physiologic increases in GH. Recent data from a large, randomized, placebo-controlled multicenter trial with GHRH1-44 demonstrate highly significant effects to reduce VAT >15% with the achievement of physiologic IGF-I levels. In addition, GHRH1-44 improved lipid parameters significantly. GHRH1-44, in contrast to recently published reports of GH, was well tolerated, without effects on insulin or glucose, even among those with impaired glucose tolerance at baseline. Taken together, these data strongly suggest that HIV-infected patients with central fat accumulation will have reduced GH secretion that is in part a function of reduced GHRH. Physiologic augmentation with GHRH is thus logical and now shown to be highly efficacious. Despite significant recent advances shown in large trials utilizing GHRH to reduce visceral adiposity and improve lipids in the HIV population, much remains to be learned regarding the use of this novel strategy in the HIV population: For example, important questions of physiology remain: 1) does GHRH1-44 therapy normalize GH pulse secretion 2) why are the effects of GHRH1-44 on visceral fat so potent for a relatively modest effects on IGF-I? 3) do the effects of GHRH1-44 on VAT result, in part, from normalized endogenous GH secretion? In addition, critical effects of GHRH on other fat depots, including muscle and liver have yet to be characterized. Effects to reduce visceral fat may also actually improve insulin sensitivity in the long run, especially as the increase in GH secretion is physiologic, and filtered through the pituitary, which is subject to feedback inhibition by IGF-I and produces physiological increases in GH, which may be less directly antagonistic to insulin. Furthermore, the effects of GHRH1-44 on direct measures of insulin sensitivity have not been investigated using the sensitive euglycemic clamp procedure. Importantly, the effects of GHRH1-44 on clinical CV risk markers, including endpoints such as IMT have not been investigated. The Aims proposed in the grant renewal will answer critical unanswered questions regarding the mechanisms of reduced GH secretion and potential clinical utility of GHRH1-44 in the HIV population. PUBLIC HEALTH RELEVANCE: In this grant we will study how the secretion of growth hormone is regulated in HIV patients. We will also investigate whether the use of a secretory factor that induces the body to makes its own GH, growth hormone releasing hormone, will improve cardiovascular risk endpoints, including abdominal fat, insulin, and carotid IMT.